PROJECT SUMMARY The results of this proposal are likely to develop knowledge for improving the standard of care for treatment of head and neck squamous cell cancer (HNSCC). Of all cancers reported in the US 3-5 % are HNSCCs. Survival rates for this cancer are poor. Only about 50% of patients will survive over the 5-year period following diagnosis. Human papillomavirus (HPV) causes a subset of HNSCCs. HPV-positive (HPV+) HNSCC incidence has nearly tripled in the last 30 years. While these HPV+ HNSCCs benefit from improved survival compared to their HPV- negative (HPV-) counterparts, their increased incidence makes understanding this disease a priority. HPV- cancers suffer much worse survival, yet neither therapies nor survival have changed dramatically over the past few decades. Furthermore, both HPV+ and HPV- HNSCC patients suffer severe co-morbidities associated with current therapies; making the development of new therapies with less toxicity and tissue damage highly desirable. We have shown that an immune response is required for long-term cures of HPV+ HNSCC following standard of care cisplatin/radiation therapy (CRT). Our findings and those of others also show that tumor metabolism, and its consequent production of high lactate in the tumor microenvironment, attenuates this immune response. We recently showed that targeting HPV oncogene related changes in the metabolism-regulating mTOR pathway enhances immune-mediated tumor clearance and long-term survival in vivo, while also synergizing with CRT to enhance direct cell cytotoxicity (Coppock et al. (2013) Neoplasia 5:620-30.). Our preliminary data demonstrate that the latter may also be applicable to HPV- HNSCCs, also commonly activated in mTOR signaling. We will follow up on these important observations by: 1) further defining the mechanism by which the HPV-16 E6 oncoprotein activates metabolism by promoting the mTOR pathway 2) determining how inhibition of mTOR signaling enhances CRT-induced cytotoxicity and the CRT-initiated immune response and 3) Determining whether systemic mTOR blockade affects the immune compartment by enhancing T lymphocyte memory cell differentiation to improve therapeutic efficacy. Potential impact: We expect that these studies will impact patient care by delineating the pathophysiology of mTOR activation in both the tumor and immune compartments of HPV+ HNSSC. The data will provide the foundation for intervening in the biology of either or both compartments. We will determine the optimal timing of an mTOR blockade that leads to the greatest improvement CRT-induced tumor clearance and overall survival rates by decreasing recurrence and metastasis. Importantly, the findings of this project could be rapidly translated into clinical trials of the appropriate disease state via the use of mTOR inhibitors currently in development.